Pinacolone → 1-(4-Chlorophenyl)-3,3-dimethylbutan-2-one

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Reaction Conditions

Reaction Steps

(a′) A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, addition funnel, heating mantle and a condenser with nitrogen inlet-outlet, is charged with 100.0 g of sodium t-butoxide and 300 mL of dry toluene. The mixture is stirred at 23-27° C. and added to a solution of 1.48 g of palladium acetate and 125.0 g of 4-bromochlorobenzene in 850 mL of dry toluene. The mixture is heated to a temperature at 95-100° C. using a heating mantle temperature set at about 95-125° C. over a period of 40 minutes. A solution of 98.1 g of pinacolone in 300 mL of toluene is added over a period of 45 minutes to 1 hour while maintaining the internal temperature at 95-100° C. The mixture is stirred for an additional 9 hours, then cooled to an internal temperature at 23-25° C. over a period of 30 minutes. Six hundred (600) g of 15% ammonium chloride solution is added over a period of 10 minutes while maintaining the internal temperature at 20-27° C. The mixture is stirred, the organic layer separated, and washed with 600 mL of saturated sodium chloride solution. The organic layer is charged into a 5 L, 4-necked, round-bottomed flask equipped with a mechanical stirrer, digital thermometer, addition funnel, heating mantle and a condenser with nitrogen inlet-outlet, and a solution of 150.0 g of L-cysteine in 900 mL of water is added. The mixture is heated to an internal temperature at 84-90° C. over a period of 40 minutes to achieve reflux, then stirred for an additional 5 hours. After cooling, the aqueous layer is removed, and the organic layer filtered over a Buchner funnel containing a pad of 20.0 g of Celite. After washing the Celite pad with 200 mL of toluene, and saving the filtrate, to the filtrate is added a solution of 75.0 g of L-cysteine and 2.5 g of sodium thiosulfate pentahydrate in 600 mL of water. The mixture is heated to an internal temperature at 78-82° C. White solids formed gradually. The triphasic mixture is stirred at this temperature for an additional 5 hours, then cooled, and the organic layer is separated. The organic layer is filtered over a pad of 20.0 g of Celite and the pad is washed with 200 mL of toluene. The combined filtrates is washed again with 400 mL of saturated NaCl solution. The organic layer is filtered and concentrated to collect about 800 mL of solvent to afford about 1.0 L of crude 1-(4-chlorophenyl)-3,3-dimethyl-2-butanone in toluene, which is used directly in the next step, theoretical Yield: 137.6 g (Pd 2 ppm).

Provenance & Evidence